Protein found in yeast and humans appears to play key role in regulating cell growth

What do humans have in common with yeast ñ that lowly, single-celled organism best known for its role in making beer and bread?

Plenty, according to researchers at Seattle's Fred Hutchinson Cancer Research
Center, who have found that humans and yeast share a protein that appears to play a key role in regulating cell growth.

Ronald Reeder, Ph.D., a member of the Hutchinson Center's Basic Sciences
Division, heads the group that published the results of this work earlier this week in the Proceedings of the National Academy of Sciences (Early Edition No. 12). Co-authors on the paper are research associate Beth Moorefield, Ph.D., and biocomputing specialist Elizabeth Greene, Ph.D., both of the Hutchinson Center.

The protein, called Rrn3, may play a pivotal role in the chain of events that
determines how fast cells grow.

"For a protein to be functionally conserved from yeast all the way up to humans
implies there must be a reason that it has been preserved from an evolutionary
standpoint," Reeder says. "We know that if you don't have this protein, you don't grow. Even if there are other mechanisms that human cells use to regulate cell growth, the fact that this one is so well conserved in humans means it's an important piece of the puzzle in our understanding of growth control."

While Reeder and colleagues are primarily excited about this fundamental new
understanding of the molecular mechanisms that trigger cell growth, the discovery that Rrn3 functions in humans as well as yeast may have several long-range benefits.

This regulatory molecule may be a unique drug target, as disabling it might halt
the growth of cancer cells. The protein also might be used as a biomarker to develop highly sensitive cancer-screening methods, as the activity of Rrn3 is expected to mirror the rate of cell growth throughout the body.

"If you were looking at the thymus or the liver, for example, and wanted to
distinguish cells that were doing normal things vs. cells that have lost control and gone haywire, the activity of this protein may be a very sensitive indicator of the uncontrolled cell growth characteristic of cancer," says Reeder, also an affiliate professor of zoology at the University of Washington.

Because of its potential commercial applications, Reeder and colleagues have
filed a patent application on the gene that produces Rrn3.

The protein appears to be a key player in an as-yet-unidentified cell-signaling
pathway that results in cell growth. Reeder theorizes that Rrn3 may act as the "on" switch that instructs RNA polymerase I, the enzyme responsible for reading the genetic code, to pump out lots of ribosomal RNA, which is part of the cellular workbench that makes the proteins necessary for cell growth. The more ribosomal RNA produced, the faster the cell grows.

"Rrn3 is absolutely essential to RNA polymerase I activity," Reeder says. "When
the polymerase is really active and churning out ribosomal RNA, the Rrn3 binds to it. But when the activity slows down, the Rrn3 detaches, which is why we think this protein is directly linked to a crucial cell-signaling pathway."

Understanding how this pathway works in the growth of yeast will be crucial to
unlocking the mystery of the process in humans.

"This finding really focuses our attention," he says. "There's a lot of machinery in
the cell to study. It's all interesting, but this is one area that's really worth exploring further."

This research was funded by a grant from the National Institute of General
Medical Sciences, a branch of the National Institutes of Health.

Editor's note: Copies of the paper, "RNA polymerase I transcription factor Rrn3 is functionally conserved between yeast and human," are available to reporters from the PNAS Office of News and Public Information, (202) 334-2138 or at pnasnews@nas.edu.

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The Fred Hutchinson Cancer Research Center is an independent, nonprofit research institution dedicated to the development and advancement of biomedical technology to eliminate cancer and other potentially fatal diseases. Recognized internationally for its pioneering work in bone-marrow transplantation, the Center's four scientific divisions collaborate to form a unique environment for conducting basic and applied science. The Hutchinson Center is the only National Cancer Institute-designated comprehensive cancer center in the Pacific Northwest. For more information, visit the Center's Web site at <www.fhcrc.org>.

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